addressing the under-reporting of adverse drug reactions...
TRANSCRIPT
RESEARCH ARTICLE
Addressing the under-reporting of adverse
drug reactions in public health programs
controlling HIV/AIDS, Tuberculosis and
Malaria: A prospective cohort study
Yohanna Kambai Avong1*, Bolajoko Jatau1, Ritmwa Gurumnaan1, Nanfwang Danat1,
James Okuma1, Istifanus Usman1, Dennis Mordi1, Blessing Ukpabi1, Gbenga
Ayodele Kayode1, Saswata Dutt1, Osman El-Tayeb2, Bamgboye Afolabi3, Isah Ambrose4,
Oche Agbaji5, Adeline Osakwe6, Ali Ibrahim7, Comfort Ogar7, Helga Nosiri7, Eunice
B. Avong8, Victor Adekanmbi9, Olalekan Uthman10, Alash’le Abimiku1, Yetunde O. Oni7,
Charles Olalekan Mensah1, Patrick Dakum1, Kamau Edward Mberu11, Olumide A.
T. Ogundahunsi11
1 Institute of Human Virology, Nigeria, Maina Court, Central Business District, Abuja, Nigeria, 2 Demian
Foundation of Belgium, Ibadan, Oyo State, Nigeria, 3 Health, Environment and Development Foundation,
Lagos State, Lagos, Nigeria, 4 Faculty of Pharmaceutical Sciences, University of Benin, Benin City, Edo
State, Benin, Nigeria, 5 Jos University Teaching Hospital, Jos, Plateau State, Nigeria, 6 University of Nigeria,
Nsukka, Anambra State, Nigeria, 7 National Agency for Food and Drug Administration and Control, Federal
Capital Territory, Abuja, Nigeria, 8 Wise Health Services Limited, Wuse, Abuja, Nigeria, 9 Division of
Population Medicine, Cardiff University, Cardiff, United Kingdom, 10 Warwick Medical School, University of
Warwick, Coventry United Kingdom, 11 Special Program for Research in Tropical Diseases, World Health
Organization (TDR), Geneva, Switzerland
Abstract
Background
Adverse Drug Reactions (ADRs) are a major clinical and public health problem world-wide.
The prompt reporting of suspected ADRs to regulatory authorities to activate drug safety
surveillance and regulation appears to be the most pragmatic measure for addressing the
problem. This paper evaluated a pharmacovigilance (PV) training model that was designed
to improve the reporting of ADRs in public health programs treating the Human Immunodefi-
ciency Virus (HIV), Tuberculosis (TB) and Malaria.
Methods
A Structured Pharmacovigilance and Training Initiative (SPHAR-TI) model based on the
World Health Organization accredited Structured Operational Research and Training Initia-
tive (SOR-IT) model was designed and implemented over a period of 12 months. A prospec-
tive cohort design was deployed to evaluate the outcomes of the model. The primary
outcomes were knowledge gained and Individual Case Safety Reports (ICSR) (completed
adverse drug reactions monitoring forms) submitted, while the secondary outcomes were
facility based Pharmacovigilance Committees activated and health facility healthcare work-
ers trained by the participants.
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 1 / 14
a1111111111
a1111111111
a1111111111
a1111111111
a1111111111
OPENACCESS
Citation: Avong YK, Jatau B, Gurumnaan R, Danat
N, Okuma J, Usman I, et al. (2018) Addressing the
under-reporting of adverse drug reactions in public
health programs controlling HIV/AIDS,
Tuberculosis and Malaria: A prospective cohort
study. PLoS ONE 13(8): e0200810. https://doi.org/
10.1371/journal.pone.0200810
Editor: Albert Figueras, Universitat Autonoma de
Barcelona, SPAIN
Received: September 21, 2017
Accepted: July 3, 2018
Published: August 22, 2018
Copyright: © 2018 Avong et al. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper and its Supporting Information
files.
Funding: The implementation of the Structured
Pharmacovigilance and Training Initiative received
financial support from the Special Programme for
Research and Training in Tropical Diseases co-
sponsored by United Nations International
Children’s Emergency Fund (UNICEF), United
Nations Development Programme (UNDP), the
Results
Fifty-five (98%) participants were trained and followed up for 12 months. More than three
quarter of the participants have never received training on pharmacovigilance prior to the
course. Yet, a significant gain in knowledge was observed after the participants completed a
comprehensive training for six days. In only seven months, 3000 ICSRs (with 100% com-
pleteness) were submitted, 2,937 facility based healthcare workers trained and 46 Pharma-
covigilance Committees activated by the participants. Overall, a 273% increase in ICSRs
submission to the National Agency for Food and Drug Administration and Control (NAF-
DAC) was observed.
Conclusion
Participants gained knowledge, which tended to increase the reporting of ADRs. The
SPHAR-TI model could be an option for strengthening the continuous reporting of ADRs in
public health programs in resource limited settings.
Background
Adverse Drug Reactions (ADRs) have emerged as a major clinical and public health problem
responsible for approximately 5 to 35% of hospital admissions in both developed and develop-
ing countries [1–7]. In the United States and Europe, ADRs are among the top ten causes of
mortality as well as increasing the cost of care [4, 8, 9 and 10]. In African countries, the intro-
duction of antiretroviral therapy (ART) for the control of HIV/AIDS has led to an upsurge in
the cardio-metabolic disorders such as type 2 diabetes mellitus and hypertension. Anti-retrovi-
ral drugs–the primary agents in ART, are largely responsible for the rise in cardio-metabolic
disorders in sub-Saharan Africa according to some authors [11, 12]. Similarly, the treatment of
Drug Resistant Tuberculosis (DRTB) with Second line Anti-tuberculosis drugs (SLDs) is driv-
ing the rise of mental illnesses (psychosis), loss of hearing (ototoxicity) and kidney damage in
some countries [13].
Prompt reporting of ADRs to drug regulatory bodies is an important drug safety measure
but under-reporting is a major challenge even in developed countries with adequate human
and material resources to tackle the problem [4, 8, 9 and 10]. A systematic review of 37 studies
by Hazell and Shakir found a median under-reporting rate of 94% [14]. Many factors are asso-
ciated with the under-reporting of ADRs [15]; the commonest factors frequently cited in most
of the studies are healthcare workers’ lack of knowledge and poor attitude [16–29]. In a very
recent study; Terblanche et al [30] found that 53.8% of the participants gave not “knowing
how to report” ADRs as the reason discouraging the reporting. Interestingly, some studies
have shown that training could address both the poor attitude and the lack of knowledge lead-
ing to increase in the accuracy and rate of reporting of ADRs to regulatory bodies [14, 31].
Prompt reporting is pragmatic and arguably, the best method for drug safety surveillance
[32]. The delay in reporting ADRs can be catastrophic; for example, almost seven million
patients took Fenfluramine before its association with Valvular Heart Disease (VHD) was
reported and the drug withdrawn from the market [33]. Similarly, over 10,000 children in Ger-
many in the early sixties suffered Phocomelia before the causative agent; Thalidomide was
identified and withdrawn from clinical practice [34].
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 2 / 14
World Bank and World Health Organization (Grant
number B40396). The funder did not have a role in
the study design, data collection and analysis,
decision to publish, or preparation of the
manuscript. The views expressed in this
publication are entirely those of the authors and do
not in any way represent those of their affiliated
institutions. Wise Health Services Limited did not
play a role in the study design, data collection and
analysis, decision to publish, or preparation of the
manuscript and only provided financial support in
the form of the salary of Eunice Bosede Avong, a
co-author. The author roles have been updated, in
the Author Contributions section of the online
submission form. The funder provided support in
the form of salaries for authors [Olumide and
Edward], but did not have any additional role in the
study design, data collection and analysis, decision
to publish, or preparation of the manuscript. The
specific roles of these authors are articulated in the
‘author contributions’ section.
Competing interests: The authors including those
affiliated with commercial organization declare that
they have no competing interest. The affiliation with
Wise Health Services Limited does not alter our
adherence to PLOS ONE policies on sharing data
and materials (as detailed online in our guide for
authors, http://journals.plos.org/plosone/s/
competing-interests).
Public health programs, especially the HIV/AIDS, Tuberculosis and Malaria have the great-
est risk of ADRs because millions of people are treated with a wide range of drugs, some of
which have serious/life threatening adverse reactions [35–38]. In the western countries where
ARVs have been used for many years, cases of rising obesity, weight gain and cardio-metabolic
diseases are persistently being reported in association with the use of ARVs [39–40]. The
demand for drug safety surveillance has therefore become a major consideration in the global
scale up of ART to end HIV/AIDS and TB. For instance, the World Health Organization
(WHO) requires countries adopting the “shorter regimen” in the control of DRTB to institute
active drug safety monitoring (aDSM).
The pharmacovigilance system in Nigeria
Pharmacovigilance systems (PVS) refer to schemes that are established to facilitate the report-
ing of suspected ADRs to national or international bodies responsible for the monitoring of
drug safety and regulations. Countries participating in the international drug monitoring
scheme are required by regulation to collect and submit their reports to the International Drug
Monitoring Center in Geneva.
Nigeria joined the International Drug Monitoring Scheme in 2004 and became the 74th
member country. The National Agency for Food and Drug Administration and Control
(NAFDAC)–the body responsible for drug safety and regulation in Nigeria, thereafter, devel-
oped a National Pharmacovigilance Policy and instituted an administrative structure, consist-
ing of the National Pharmacovigilance Center (NPC) in Abuja and Zonal Pharmacovigilance
Centers (ZPC) in each of the six geopolitical regions of the country.
NAFDAC also instituted the National Pharmacovigilance System which involves signal
detection, collection, collation and analysis of ADRs [41]. Organizations or individuals holding
a marketing authorization for marketing medicinal products are mandated to report any sus-
pected ADR associated with the product they are authorized to market [41]. Healthcare pro-
viders (pharmacists, doctors and nurses) are also required by the government to report
suspected ADRs, although this is not mandatory [41] as is the case in Sweden, France and Italy
[42].
The primary tool for reporting ADRs in Nigeria is a structured in-take form known as the
“Adverse Drug Reactions Form” (ADR Form) (Figure A in S1 File) available at https://www.
nafdac.gov.ng. This form is similar to the United Kingdom’s Yellow Card and has five major
sections, which must all be accurately completed. A fully completed ADR form is known as the
“Individual Case Safety Report” (ICSR).
The quality of an ICSR is directly proportional to the amount of clinically relevant informa-
tion that is included [43–46]. On this basis, an ICSR with 100% completeness is expected to
have the highest quality provided that the information included in all the sections is accurate.
In Nigeria, poor quality ICSRs are usually quarantined by the NPC as they cannot be sent to
the International Drug Monitoring Center in Uppsala, Sweden.
A typical ICSR provides the following information:
a. Patient details (name, age, sex and weight)
b. Adverse drug reaction (description, date reaction started and stopped and outcome–recov-
ered fully, congenital abnormality, recovered with abnormality, life threatening and death)
c. Suspected drug (brand and generic names, batch number, NAFDAC number, expiry date)
d. Concomitant medicines (all medicines taken in the last three months)
e. Source of report
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 3 / 14
The reporting of ADRs to NAFDAC follows two major steps:
a. Accurate completion of the ADR forms when a suspected ADR is observed by healthcare
providers or reported by a patient during routine treatment of health conditions. Marketing
Authorization Holders (MAH) are also expected to complete the ADR forms when sus-
pected ADR are reported to them by patients, health institutions or the healthcare workers
within and outside the country.
b. Dispatch the ICSRs to the NPC in Abuja.
The ICSRs are dispatched to the NPC in Abuja through different means; the frequently
used method is surface mail posting of the ICSRs to the NPC by the health facilities or visiting
the health facilities by the NAFDAC designated staff to pick up the ICSRs. ICSRs could also be
scanned and sent as “attachment” through emails communication. The NPC validate and ana-
lyze the submitted ICSRs and extract the relevant information into VigiBase–a proprietary
web database (https://www.who-umc.org/vigibase/vigibase/) hosted at the WHO collaborating
center for international drug monitoring in Uppsala, Sweden.
The pervasive problem of under-reporting of adverse drug reactions in
Nigeria
The under-reporting of ADRs in Nigeria has been documented in several studies [47–50].
According to NAFDAC, only 16,500 ICSRs out of 80,000 ADR Forms distributed nation-wide
for 12 years (2004 to 2016), were submitted back to NAFDAC [51]. This is equivalent to sub-
mitting only 1,375 ICSRs per year. The WHO criteria for adequate reporting of ADRs are 200
reports per million inhabitants per year [52]. With a population of 170 million inhabitants in
2016, at least 34,000 ICSRs should have been submitted to NAFDAC instead of the 1,375
ICSRs. Furthermore, Nigeria had 323,941healthcare workers [53–54] (consisting of Physicians,
Nurses, Midwives, Pharmacists, Pharmacy-technicians, Radiographers, Medical Laboratory
Scientists and Community Health Officers), [55–56] according to the 2005–2007 report of the
National Professional Medical/Health Regulatory bodies. In 2015, NAFDAC reported that
only 1,385 ICSRs (see Figure B in S1 File) were submitted supposedly by over 323,941 workers.
Given the large population of healthcare workers and the overwhelming increase in drug con-
sumption due to the high burden of HIV/AIDS, Tuberculosis and Malaria, submitting only
1,385 ICSRs clearly suggests that Nigeria is facing a major crisis of under-reporting of ADRs.
Ironically, the factors that are undermining the reporting of ADRs in other countries are also
rife in Nigeria and these include lack of knowledge, inaccurate description of ADRs, poor qual-
ity reports and poor compliance to the pharmacovigilance processes (data collection, storage,
management, risk assessment and communication) [14,41,44].
The SPHAR-TI model was designed to address the challenge of under-reporting of ADRs in
Nigeria through capacity building. Until the SPHAR-TI course, majority (71.0%) of the health-
care workers that participated in the course have never received training in pharmacovigilance
but were nonetheless working in public health institutions or hospitals directly treating HIV/
AIDS, Tuberculosis and Malaria through the respective public health disease control programs.
Some studies have reported high prevalence of ADRs emanating from the HIV/AIDS, TB and
Malaria public health programs [13, 35, 37, 38, 39, 40], thus, justifying the SPHARTI model.
The structured pharmacovigilance and Training Initiative model
The SPHAR-TI model (refer to S2 File) was a 12 month modular course, modelled after the
WHO accredited Structured Operational and Training Initiative (SORT-IT) [57,58]. The
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 4 / 14
model incorporated six distinct but inter-related activities, referred to as the SPHAR-TI’s prin-
ciples. These are: a training workshop; participants’ mobilization; monitoring and evaluating
and providing feedback; setting up a reporting system; providing leadership and collaborating
with the government. This paper evaluated the model with the main objective of describing
the outcomes after the first 12 months of implementation.
Methods
This manuscript complies with the STROBE reporting standard for observational studies.
Ethics approval
Ethics approval for the evaluation was given to the Institute of Human Virology Nigeria by the
National Health Research Ethics Committee of Nigeria under the title: “Engaging indigenous
organization to sustain and enhance clinical services for the prevention, care and treatment of
HIV/AIDS in the Federal Republic of Nigeria under the President’s Emergency Plan for AIDS
Relief (PEPFAR)”; Number: NHREC/01/01/2007; dated August 12, 2016.
Setting
The workshop was conducted in the Federal Capital Territory, Abuja but the participants were
selected from health facilities and institutions in the six geopolitical regions of Nigeria. Nigeria
has six geopolitical regions with a population of 170 million inhabitants. These regions include
the North-east, North-west, North-central, South-west, South-east and South-south.
Study population
The study population consisted of health care workers (Nurses, Physicians and Pharmacists)
who were selected for the SPHAR-TI course based on rigorous selection criteria (Table A in
S2 File).
Study design
A prospective cohort design was deployed for the evaluation of the SPHAR-TI model. Partici-
pants that attended the SPHAR-TI’s workshop described in S2 File were followed up for 12
months through internet and telephone communication. Performance was evaluated based on
meeting defined milestones. Bio-demographic characteristics were recorded and participants’
knowledge assessed prior to the workshop. Five days after the workshop, participants’ knowl-
edge was re-assessed without giving them a prior warning they would be re-assessed. ICSRs
were submitted online every three months (31st May, 29th July, 30th September and 30th
November 2016). Data on the number of healthcare workers trained by the participants and
the Pharmacovigilance Committees activated were submitted online not later than 10th
December 2016.
Outcomes of measure
The aim of the model was to improve the reporting of ADRs from both hospitals based and
more importantly, community based public health programs controlling the AIDS epidemic,
Tuberculosis and Malaria. The primary outcomes were knowledge gained and the number of
ICSRs submitted to NAFDAC. We expected to see a significant gain in knowledge and a
remarkable increase in the reporting of ADRs if the model was effective. The secondary out-
comes were the health facility staff trained by the participants through the step-down training
and the Pharmacovigilance Committees activated.
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 5 / 14
The secondary outcomes were evaluated because NAFDAC encourages the setting up of
Pharmacovigilance Committees in health facilities as a pragmatic strategy for promoting the
reporting of ADRs. During the workshop, participants were taught and encouraged to step-
down the workshop and activate the committees. We expected the participants to be able to
train others and set up new Pharmacovigilance Committees if the model was effective.
Evaluation of the outcomes of the model
The overall outcome of the model was assessed by comparing the number of ICSRs submitted
by the national health workforce in seven months with the number submitted by the partici-
pants in seven months. The primary and secondary outcomes were evaluated as described
below:
Gain in knowledge. Gain in knowledge was assessed using a structured questionnaire,
consisting of 24 questions developed by expert physicians and pharmacists in the three diseases
(HIV, TB and Malaria). The questions covered the clinical management of HIV/AIDS, Tuber-
culosis and Malaria and the ADRs associated with the use of antiretroviral, anti-tuberculosis
and anti-malaria drugs. The questionnaire also assessed the knowledge of Nigeria’s ADR
reporting and pharmacovigilance system.
Prior to the commencement of the workshop, the questionnaire was administered for an
hour (pre-test). At the end of the workshop, which was five days after the pre-test, the same
questionnaire was re-administered (post-test). To minimize measurement biases, the ques-
tionnaire was withdrawn immediately after the pre-test and participants were not warned the
questionnaire would be re-administered after the workshop. Participants did not also know
the result of the pre-test until after the post-test. The pass mark for the pre and post-tests was
45%.
Individual case safety reports submission. The correctness and completeness of the
ICSR and the quantities submitted online were assessed. All submitted ICSRs were manually
checked for correctness and completeness and the total number of correctly completed forms
were counted and recorded in each cycle. The number of ICSRs submitted within seven
months were summed up and compared with the amount that would have been submitted by
the national health workforce in seven months in 2015.
Pharmacovigilance committees activated and training of health facility staff by partici-
pants. To assess the two variables, participants were given a spreadsheet for recording their
step-down activities after the workshop. The spreadsheet included the following variables:
a. Status of the health facility
b. Date of training
c. Description of training
d. Objectives of the training
e. Mode of delivery of training content
f. Number of doctors, nurses and pharmacists in attendance
g. Number of Pharmacovigilance Committees activated
h. Involvement of hospital management
i. Collaboration with a pharmaceutical company in the training
j. Collaboration with NAFDAC.
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 6 / 14
The completed spreadsheets were submitted to NAFDAC online at different times but not
later than 10th December, 2016. We extracted the number of health facility staff trained and
the number of Pharmacovigilance Committees’ activated into a template for analysis.
Statistical analysis
We applied descriptive statistics (mean, percentage and summation) in the analysis of the bio-
demographic data and primary and secondary outcomes. The overall outcome of the model
was analyzed by calculating the percentage increase in ADR submission using the arithmetic
formula: T-M/M�100 [Where T = total number of ICSRs submitted by the participants in
seven months; M = total number of ICSR submitted by the national health workforce in seven
month]. According to NAFDAC, in 2015, the over 323,941 national health workforce submit-
ted 1,385 ICSRs (refer to Figure B in S1 File), equivalents to 805 ICSRs in seven months. The
3000 ICSRs (T) (submitted by the participants) and 805 ICSRs (M) were plucked into the
arithmetic formula to determine the percentage increase in ICSRs submission.
Participants gain in knowledge was analyzed by calculating the difference between the
mean pre-test and post-test scores. Summation was applied in analyzing the number of ICSR
submitted by the participants, health staff trained by the participants and Pharmacovigilance
Committees activated.
Results
Two hundred and forty seven candidates applied for the course, 56 met the selection criteria
and were invited for the workshop but one person could not make it leaving 55 participants,
equivalent to 98.2% (55/56) participating rate. Participants’ characteristics are presented in S1
Table. Participants without a previous training in pharmacovigilance were more in number
compared with participants that have attended pharmacovigilance training (s) in the past [39
(71%) vs 16 (29.1%)].
S2 Table compares the difference in the mean scores (gain in knowledge) among the partic-
ipants. Participants more than 40 years (9.4 [SD = 7.0]), Pharmacists (8.5 [SD = 7.4]), and
Nurses (7.6 [SD = 6.4]), participants from the Roll Back Malaria program (9.3 [SD = 8.8]) and
those without previous training (9.5 [SD = 7.8]), appeared to gain knowledge more than par-
ticipants from other groups.
The outcomes of the model are presented in the S3 Table. Participants demonstrated a sig-
nificant gain in knowledge (20.4 vs 27.8 (P value < 0.001) and submitted 3000 ICSRs with
100% correctness and completeness. Compared with the 805 ICSRs submitted by more than
323,941 healthcare workers in the general population who were not SPHAR-TI trained, the
percentage increase in ICSRs submission was 273%. Participants were also able to indepen-
dently train 2,937 healthcare workers and activated 46 Pharmacovigilance Committees.
Discussion
The major finding of this evaluation is the significant gain in knowledge observed among the
participants generally. NAFDAC’s concordance on the effectiveness of the model to signifi-
cantly improve the reporting of ADRs in Nigeria (Figure B in S1 File) buttresses this observa-
tion and underscores the potential viability of the model to improve the reporting of ADRs in
public health programs. Furthermore, the positive outcome achieved when NAFDAC tested
the model in the training of 600 healthcare workers from ten states in Nigeria (Figure B in S1
File), suggests that the model can be replicated in countries facing similar challenge of under-
reporting of ADRs with Nigeria.
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 7 / 14
We also observed four additional outcomes. Firstly, participants developed the capacity to
detect and accurately report ADRs including the serious ADRs such as Stevens Johnson Syn-
drome (SJS) and Bilateral Gynaecomastia (BG). Secondly, the rate of ADR reporting increased
by 273%, when compared with the average reporting rate in the general population over the
past 12 years. This finding is consistent with the findings from previous studies that examined
the impact of training at improving the reporting of ADRs [31, 59]. Thirdly, participants were
able to train their peers, thus, they increased the number of healthcare workers for pharmacov-
igilance service delivery particularly in the communities. In addition, participants developed
the capacity to activate Pharmacovigilance Committees in their various health facilities. This is
a feat NAFDAC has persistently encouraged in an effort to boost the reporting of ADRs in
Nigeria.
We also observed two unintended outcomes of the application of the SPHAR-TI’s model.
The first is the detection and reporting of SJS and BG by some participants. SJS is a fatal ADR
associated with the use of Nevirapine, a popular antiretroviral drug that constitutes the back-
bone of first line antiretroviral regimen. This finding confirms that Nigerians are also suscepti-
ble to the SJS of Nevirapine as reported in other climes. Further analysis of the submitted
ICSRs might reveal other life threatening ADRs in the Nigerian population, which the
National Agency for the Control of AIDS (NACA) need to pay close attention to. The second
outcome is the interplay of several factors resulting to the increase in the reporting of ADRs.
The model combined at least six factors: training, mobilization of participants with resources
(refer to Figures A-D in S2 File), a practical reporting system, monitoring and evaluation and
providing feedbacks and effective leadership. There is no gainsaying in concluding that train-
ing alone without the other factors could not have yielded the results we have reported. Per-
haps, the reason Nigeria and other countries are not able to significantly address the challenge
of under-reporting of ADRs despite the abundance of training may be the over-reliance on
training alone without the other factors.
We observed a surprised finding in the evaluation (S3 Table). Participants without prior train-
ing tended to gain knowledge more than those who have attended pharmacovigilance trainings.
The same tendency was observed among the health care workers, with pharmacists and nurses
gaining knowledge more than the medical doctors. We do not have a viable reason for this but we
suspect that personal commitment and seriousness may have led to the difference.
The model holds an important lesson for sub-Saharan Africa (SSA), which has the largest
public health programs treating millions of people with HIV, Tuberculosis and Malaria. Cur-
rently, over 20 million people must be placed on antiretroviral drugs according to the new
WHO treatment guidelines for HIV [60]. The risk of “antiretroviral therapy associated ADRs”
is expected to be higher in this region than any other region in the world. Evidence from stud-
ies conducted in developed countries where antiretroviral therapy has been offered for many
years have reported a rise of cardiometabolic disorders like type 2 diabetis mellitus and cardio-
vascular disease [61–65], which have long been associated with the antiretroviral medications.
In the Drug Resistant Tuberculosis public health program, hearing loss associated with the use
of the injectable aminiglycosides (Amikacin and Kanamycin) is a major clinical challenge [66–
67] and yet, thousands of patients are using these drugs in the communities. As sub-Saharan
African countries continue to scale-up public health treatment programs in a wider global
effort to end HIV and Tuberculosis, the prevalence of ADRs will continue to increase, justify-
ing the need for the training of healthcare providers for ADRs reporting.
Another factor that favors the training of healthcare providers for ADR reporting, which
justifies the use of the SPHAR-TI model, is the acute shortage of healthcare workers in Africa.
The “Brain Drain” report by Rebecca Coombes showed that the number of healthcare workers
in many African countries is shrinking [68]. Ghana with a total population of 20 million
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 8 / 14
people has only 1500 medical doctors and more than two-third of young Ghanaian doctors
leave the country within three years of graduation. In Mozambique, a nation of similar size
with Ghana, there are only 500 medical doctors [68]. Malawi has a worse situation; there are
12 million people but only 350 medical doctors are available to cater for all the health needs
including the reporting of ADRs [68]. Nigeria appears to have the highest density of healthcare
workers in Africa [37–54] but the large population size and the lack of capacity for reporting
ADRs are major constrains. However, the training of healthcare workers as has been shown in
several studies can improve the reporting of ADRs. The WHO in its 2013 report on “research
for universal health coverage”, highlighted the need for training of healthcare workers in pub-
lic health programs close to the supply and demand side of health services [69]. The structured
pharmacovigilance capacity building model that we have evaluated addresses this gap in
response to the WHO recommendation.
An important piece of information the SPHAR-TI model has demonstrated is that short
training alone is not sufficient to stem the tide of under-reporting of ADRs. In fact, most devel-
oping countries, including Nigeria, provide trainings to healthcare workers to boost the
reporting of ADRs but the crisis of under-reporting is not going away. What may be lacking
are some of the factors the SPHAR-TI model seems to illustrate, which include: poor mobiliza-
tion of healthcare providers, a weak monitoring and evaluation with complete absence of feed-
back mechanisms when ICSRs are submitted to central regulatory authorities, lack of a clear
and practical means of submitting ICSRs, lack of private-public collaboration, weak leadership
and low motivation of the workforce. If all these factors are combined appropriately, the
reporting of ADRs could significantly increase.
The model has some limitations that need to be considered alongside the positive outcomes.
The participants were practicing doctors, nurses and pharmacists with some experience in the
pharmacotherapy of AIDS, tuberculosis and malaria. This knowledge may have contributed to
the knowledge gained through the SPHAR-TI training. This argument may however not hold
true because the medical doctors expected to have the highest level of knowledge and should
have demonstrated higher scores in the post-test compared to the pharmacists and nurses actu-
ally scored less. The age of the participants is another factor; majority of the participants were
mid-career professionals occupying lower positions of responsibilities and were likely to be less
busy and quick learners. Elderly people with many social and professional responsibilities and
perhaps with a “slow to learn” disposition would probably have performed poorly. But again,
the results in S2 Table demonstrate that participant over 40 years scored higher marks than the
younger people within the age bracket of 30–39 years. Overall, the long term impact of the
model need to be assessed; our findings in this study are only limited to the period of evaluation,
which is between 10 to 12 months. However, despite these limitations, the SPHARTI model has
provided an option for improving the reporting of ADRs in resource limited settings.
We are recommending the use of the SPHAR-TI’s model to minimize the worrisome
under-reporting of ADRs in the developing world. As stated earlier, under-reporting of ADRs
prevents drug safety monitoring and regulation, which adds to the disease burden and mortal-
ity. Nigeria and other developing countries may not be able to absorb additional health chal-
lenges caused by ADRs as these countries are already overstretched by communicable and
non-communicable diseases. The SPHAR-TI model may be an effective approach that would
complement existing models of ADRs reporting in Africa and elsewhere.
Conclusion
The systematic and output driven training and follow-up of healthcare providers had a positive
impact on the reporting of ADRs. The SPHAR-TI principles effectively contributed to the
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 9 / 14
success of the model and are recommended to institutions or organizations providing pharma-
covigilance services in Africa and other regions with similar settings.
Supporting information
S1 File. Figure A: Adverse Drug Reactions Form; Figure B: Letter of appreciation in respect
of collaborative work to increase adverse drug reactions reporting in Nigeria.
(DOCX)
S2 File. Protocol of the Structured Pharmacovigilance and Training Initiative.
(DOCX)
S1 Table. Participants’ characteristics, N = 55.
(DOCX)
S2 Table. Association between post test scores and participants’ characteristics.
(DOCX)
S3 Table. The outcomes of the SPHAR-TI model.
(DOCX)
S1 Dataset. S1 DATA.xls.
(XLSX)
S2 Dataset. S2 DATA.xls.
(XLSX)
S3 Dataset. S3 DATA.xls.
(XLSX)
S4 Dataset. S4 DATA.xls.
(XLSX)
S5 Dataset. S5 DATA.xls.
(XLSX)
Acknowledgments
All the 55 participants and the health facilities that participated in the SPHAR-TI model are
duly acknowledged. Nurse Ezekiel Dickson and Pharm. Ganiyu Abideen are acknowledged for
reporting Bilateral Gynaecomastia in adult men and Stevens Johnson Syndrome at the Abuba-
kar Tafawa Balewa University Teaching Hospital (ATBUTH), Bauchi, Bauchi State and Gov-
ernment Chest Hospital, Jericho, Ibadan, Oyo State respectively. Also acknowledged are the
staff of the IHVN and NAFDAC who contributed to this work in diverse ways.
Author Contributions
Conceptualization: Yohanna Kambai Avong.
Data curation: Bolajoko Jatau, Ritmwa Gurumnaan, Nanfwang Danat, Istifanus Usman.
Formal analysis: Yohanna Kambai Avong, James Okuma, Gbenga Ayodele Kayode.
Funding acquisition: Patrick Dakum.
Project administration: Yohanna Kambai Avong, Bolajoko Jatau, Ritmwa Gurumnaan, Nanf-
wang Danat, Istifanus Usman.
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 10 / 14
Resources: Ali Ibrahim, Yetunde O. Oni, Charles Olalekan Mensah, Patrick Dakum.
Supervision: Yohanna Kambai Avong, Bolajoko Jatau, Kamau Edward Mberu, Olumide A. T.
Ogundahunsi.
Validation: Bolajoko Jatau, Ritmwa Gurumnaan, Nanfwang Danat, Patrick Dakum.
Writing – original draft: Yohanna Kambai Avong.
Writing – review & editing: Yohanna Kambai Avong, Bolajoko Jatau, James Okuma, Dennis
Mordi, Blessing Ukpabi, Gbenga Ayodele Kayode, Saswata Dutt, Osman El-Tayeb, Bamg-
boye Afolabi, Isah Ambrose, Oche Agbaji, Adeline Osakwe, Ali Ibrahim, Comfort Ogar,
Helga Nosiri, Eunice B. Avong, Victor Adekanmbi, Olalekan Uthman, Alash’le Abimiku,
Kamau Edward Mberu, Olumide A. T. Ogundahunsi.
References1. Beijer HJ, Blaey CJ. Hospitalisations caused by adverse drug reactions (ADR): a meta-analysis of
observational studies. PharmWorld Sci. 2002; 24(2):46–54.
2. Einarson TR. Drug-related hospital admissions. Ann Pharmacother. 1993; 27(7–8):832–40. https://doi.
org/10.1177/106002809302700702 PMID: 8364259
3. Kongkaew C, Noyce PR, Ashcroft DM. Hospital admissions associated with adverse drug reactions: a
systematic review of prospective observational studies. Ann Pharmacother. 2008; 42(7):1017–25.
https://doi.org/10.1345/aph.1L037 PMID: 18594048
4. Lazarou J, Pomeranz BH, Corey PN. Incidence of adverse drug reactions in hospitalized patients: a
meta-analysis of prospective studies. JAMA. 1998; 279(15):1200. PMID: 9555760
5. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, et al. Adverse drug reactions as
cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004; 329(7456):15–9.
https://doi.org/10.1136/bmj.329.7456.15 PMID: 15231615
6. Paul E, End-Rodrigues T, Thylen P, Bergman U. Adverse drug reactions a common cause of hospitali-
zation of the elderly. A clinical retrospective study. Lakartidningen. 2008; 105(35):2338–42. PMID:
18831440
7. Baker GR, Norton PG, Flinto V, Blais R, Brown A, Cox J, et al. The Canadian adverse events study: the
incidence of adverse events among hospital patients in Canada. CMAJ. 2004; 170(11):1678–86.
https://doi.org/10.1503/cmaj.1040498 PMID: 15159366
8. Wiktorowicz M, Lexchin J, Moscou K. Pharmacovigilance in Europe and North America: divergent
approaches. Soc Sci Med. 2012; 75: 165–170; https://doi.org/10.1016/j.socscimed.2011.11.046 PMID:
22521677
9. Kiguba R, Karamagi C, Bird SM. Incidence, risk factors and risk prediction of hospital-acquired sus-
pected adverse drug reactions: a prospective cohort of Ugandan inpatients. BMJ open. 2017; 7:
e010568; https://doi.org/10.1136/bmjopen-2015-010568 PMID: 28110281
10. Jemal A, Ward E, Hao Y, Thun M. Trends in the leading causes of death in the United States, 1970–
2002. JAMA. 2005; 294:1255–1259. https://doi.org/10.1001/jama.294.10.1255 PMID: 16160134
11. Dillon DG, Gurdasani D, Riha J, Ekoru K, Asiki G, Mayanja BN, et al. Association of HIV and ART with
cardiometabolic traits in sub-Saharan Africa: a systematic review and meta-analysis. Int J Epidemiol.
2013, 42: 1754–1771. https://doi.org/10.1093/ije/dyt198 PMID: 24415610
12. Mbanya JC, Motala AA, Sobngwi E, Assah FK, Enoru ST. Diabetes in sub-Saharan Africa. Lancet.
2010; 375: 2254–2266. https://doi.org/10.1016/S0140-6736(10)60550-8 PMID: 20609971
13. Avong YK, Isaakidis P, Hinderaker SG, Van den Bergh R, Ali E, Obembe BO, et al. Doing No Harm?
Adverse Events in a Nation-Wide Cohort of Patients with Multidrug-Resistant Tuberculosis in
Nigeria. PLoS ONE. 2015; 10(3): e0120161. https://doi.org/10.1371/journal.pone.0120161 PMID:
25781958
14. Hazell L, Shakir SA. Under-reporting of adverse drug reactions: a systematic review. Drug Saf. 2006;
29: 385–396. PMID: 16689555
15. Varallo FR, Guimaraes SOP, Abjaude SR, Mastroiami PC. Causes for the under-reporting of adverse
drug events by health professionals: a systematic review. Rev Esc Enferm USP. 2014; 48(4): 739–47.
PMID: 25338257
16. Inman WHW. Attitudes to adverse drug-reaction reporting. Br J Clin Pharmacol 1996; 41: 433–5.
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 11 / 14
17. van Grootheest K, Olsson S, Couper M, de Jong-van den Berg L, Pharmacists’ role in reporting adverse
drug reactions in an international perspective. Pharmacoepidemiol Drug Saf 2004 Jul; 13(7): 457.
https://doi.org/10.1002/pds.897 PMID: 15269929
18. Milstien JB, Faich GA, Hsu JP, Knapp DE, Baum C, Dreis MW, et al. Factors affecting physician report-
ing of adverse drug reactions. Drug Inf J. 1986; 20: 157–64.
19. Walker SR, Lumley CE. The attitudes of general practitioners to monitoring and reporting adverse drug
reactions. Pharm Med. 1986; 1: 195–203.
20. Robins AH, Weir M, Biersteker EM. Attitudes to adverse drug reactions and their reporting among medi-
cal practitioners. S Afr Med J. 1987; 72: 131–4. PMID: 3616786
21. Rogers AS, Israel E, Smith CR, Levine D, McBean AM, Valente C, et al. Physician knowledge, attitudes,
and behavior related to reporting adverse drug events. Arch Intern Med. 1988; 148: 1596–600. PMID:
3382304
22. Scott HD, Thacher-Renshaw A, Rosenbaum SE, Waters WJ, Green M, Andrews LG, et al. Physician
reporting of adverse drug reactions: results of the Rhode Island adverse drug reaction reporting project.
JAMA. 1990; 263: 1785–8. PMID: 2313850
23. Fincham JE. Hospital and nursing home pharmacists’ attitudes toward adverse drug reaction reporting.
J Soc Admin Pharm. 1990; 7: 117–22.
24. Bateman DN, Sanders GL, Rawlins MD. Attitudes to adverse drug reaction reporting in the northern
region. Br J Clin Pharmacol. 1992; 34: 421–6. PMID: 1467137
25. Lee KK, Chan TY, Raymond K, Critchley JA. Pharmacists’ attitudes toward adverse drug reaction
reporting in Hong Kong. Ann Pharmacother. 1994; 28: 1400–3. https://doi.org/10.1177/
106002809402801213 PMID: 7696734
26. Gram LF. Attitude and considerations of Danish physicians towards reporting of adverse drug reactions:
a questionnaire study under European direction. Ugeskr Laeger. 1995; 157: 1692–4. PMID: 7740634
27. Belton KJ, Lewis SC, Payne S, Rawlin MD, Wood SM. Attitudinal survey of adverse drug reaction
reporting by medical practitioners in the United Kingdom. Br J Clin Pharmacol. 1995; 39 (3): 223–6.
PMID: 7619660
28. Generali JA, Danish MA, Rosenbaum SE. Knowledge of and attitudes about adverse drug reaction
reporting among Rhode Island pharmacists. Ann Pharmacother. 1995; 29: 365–9. https://doi.org/10.
1177/106002809502900404 PMID: 7633012
29. Pouget-Zago P, Lapeyre-Mestre M, Bagheri H, Montastruc JL.Pharmacovigilance seen by a selected
group of general practitioners and of residents in the Midi-Pyrenees region Therapie. 1995 Sep-Oct; 50
(5):459–62.
30. Terblanche A, Meyer JC, Godman B, Summers RS. Knowledge, attitudes and perspective on adverse
drug reaction reporting in a public sector hospital in South Africa: baseline analysis. Hosp Pract,
2017:1–8.
31. Osakwe A, Oreagba I, Adewunmi AJ, Adekoya A, Fajolu I. Impact of training on Nigerian healthcare pro-
fessionals’ knowledge and practice of pharmacovigilance. Int J Risk Saf Med. 2013; 25: 219–227.
https://doi.org/10.3233/JRS-130605 PMID: 24305560
32. Wysowski DK, Swartz L. Adverse drug event surveillance and drug withdrawals in the United States,
1969–2002: the importance of reporting suspected reactions. Arch Intern Med. 2005; 165: 1363–1369.
https://doi.org/10.1001/archinte.165.12.1363 PMID: 15983284
33. Pillars PI. Clinical perspective in drug safety and adverse drug reactions. Expert Rev Clinical Pharma-
cology. 2008; 1(5): 695–705.
34. British Broadcasting Corporation World Service. What happened to Thalidomide babies? Report by
Frederick Dove, 3rd Nov. 2011. http://www.bbc.com/news/magazine-15536544. Accessed on 3rd Jul
2017.
35. Shehu NY, Ojeh VB, Osaigbovo G, Agaba P and Agbaji O. A 33-year-old patient with humanimmunode-
ficiency virus on antiretroviral therapy with efavirenz-induced complex partial seizures: a case report. J
Med Case Reports. 2016; 10:93.
36. Ogwuche LO, Ojeh VB, London IA, Naima N, Dady C, Finangwai AI, et al. Adverse drug reaction reports
in an antiretroviral treatment centre in Jos, North Central Nigeria. Br J Pharmac Res. 2014; 4(6): 714–
721.
37. Agbaji OA, Agaba PA, Ekeh PN, Sule HM, Ojoh RO, Audu E, et al. Efavirenz-induced gynaecomastia in
HIV-infected Nigerian men: A report of six cases. Journal of Medicine and Medical Sciences. 2011, 2
(11): 1221–1224.
38. Agu KA, Oparah AC. Adverse drug reactions to antiretroviral therapy: results from spontaneous report-
ing system in Nigeria. Perspectives in Clinical Research.2013, 4(2): 117–124. https://doi.org/10.4103/
2229-3485.111784 PMID: 23833736
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 12 / 14
39. Koethe JR, Jenkins CA, Lau B, Shepherd BE, Justice AC, Janet PT, et al. Rising obesity prevalence
and weight gain among adults starting antiretroviral therapy in the United States and Canada. AID Res
Hum Retroviruses. 2016; 32: 50–58.
40. Barbaro G. Metabolic and cardiovascular complications of highly active antiretroviral therapy for HIV
infection. Curr HIV Res. 2010; 4: 79–85.
41. Nigeria Federal Ministry of Health (compiled by Adetunji Labiran, Margaret Mafe, Bayo Onajole, Eyitayo
Lambo). Nigeria National Pharmacovigilance Policy and Implementation Framework. Abuja: Federal
Ministry of Health. 2008: 2–45.
42. Waller PC, Bahri P. Regulatory pharmacovigilance. Chichester: John Wiley and Sons, 2002: 183–94.
43. Bergvall T, Noren GN, Lindquist M (2014) vigiGrade: a tool to identify well-documented individual case
reports and highlight systematic data quality issues. Drug Saf; 37: 65–77. https://doi.org/10.1007/
s40264-013-0131-x PMID: 24343765
44. Clarke A, Deeks JJ, Shakir SA (2006) An assessment of the publicly disseminated evidence of safety
used in decisions to withdraw medicinal products from the UK and US markets. Drug Saf; 29: 175–181.
PMID: 16454545
45. Edwards IR, Lindquist M, Wiholm BE, Napke E (1990) Quality criteria for early signals of possible
adverse drug reactions. Lancet. 336: 156–158. PMID: 1973481
46. Lindquist M. Data quality management in pharmacovigilance. Drug Saf; 2004; 27: 857–870. PMID:
15366974
47. Chinenye JU, Michael OU. Heath workers and hospital patients’ knowledge of pharmacovigilance in
Sokoto, North-West, Nigeria. Nig J Pharmac Sci. 2012; 11 (2): 31–40.
48. Fadare JO, Enwere OO, Afolabi AO, Chedi BAZ, Musa A. Knowledge, Attitude and Practice of Adverse
Drug Reaction Reporting among Healthcare Workers in a Tertiary Centre in Northern Nigeria. Tropical
Journal of Pharmaceutical Research. 2011; 10 (3): 235–242
49. Ohaju-Obodo JO, Iribhogbe OI. Extent of pharmacovigilance among resident doctors in Edo and Lagos
states of Nigeria. Pharmacoepidemiology Drug Safety. 2010; 19(2):191–5. https://doi.org/10.1002/pds.
1724 PMID: 20014358
50. Oreagba IA, Ogunleye OJ, Olayemi SO. The knowledge, perceptions and practice of pharmacovigi-
lance amongst community pharmacists in Lagos state, south west Nigeria. Pharmacoepidemiol Drug
Safety. 2011; 20(1):30–5.
51. Speech of the Acting Director of the National Agency for Food and Drug Administration and Control,
delivered on the 3rd March, 2016 in Abuja during the occasion of declaring the SPHAR-TI Workshop
opened.
52. The importance of pharmacovigilance: safety monitoring of medicinal products. WHO-UMC 2002.
53. Nigeria Federal Ministry of Health. Health Workforce Country Profile for Nigeria, First Edition. October
2008. Abuja: FMOH. http://www.afro.who.int/index.php?option=com_docman&task=doc_download.
Accessed on 2nd July 2017
54. Adebayo O, Labiran A, Emerenini CF, Omoruyi L. Health Workforce for 2016–2030: Will Nigeria have
enough? Inter J Inn Heal Res, 2016; 4(1): 9–16.
55. World Health Organization. “The world health report: 2006: working together for health”
56. Diallo K, Zuru P, Gupta N, Dal Poz M. Monitoring and evaluation of human resources for health: an inter-
national perspective. Human resources for health. 2003; 1(1): 3. https://doi.org/10.1186/1478-4491-1-3
PMID: 12904252
57. Ramsay A, Harries AD, Zachariah R, Bissell K, Hinderaker SG, Edginton M, et al. The Structured Oper-
ational Research and Training Initiative for public health programs. Public Health Action. 2014, 4(2):
79–84 https://doi.org/10.5588/pha.14.0011 PMID: 26399203
58. Guillerm N, dar Berger S, Bissell K, Kumar AMV, Ramsay A, Reid AJ, et al. Sustained research capacity
after completing a Structured Operational Research and Training (SORT IT) course. Public Health
Action. 2016; 6(3): 207–208. https://doi.org/10.5588/pha.16.0057 PMID: 27695687
59. Lopez-Gonzalez E, Herdeiro MT, Figueiras A. Determinants of under-reporting of adverse drug reac-
tions: a systematic review. Drug Saf. 2009, 32: 19–31. https://doi.org/10.2165/00002018-200932010-
00002 PMID: 19132802
60. Ford DN, Laga M. Lifelong ART for 20 million people in sub-Saharan Africa: communities will be key for
success. The Lancet Global Health. 2014, (2): e262–e263.
61. Palella FJ Jr, Baker RK, Moorman AC, Chmiel JS, Wood KC, Brooks JT, et al. Mortality in the highly
active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study.
Journal of acquired immune deficiency syndromes. 2006; 43: 27–34 https://doi.org/10.1097/01.qai.
0000233310.90484.16 PMID: 16878047
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 13 / 14
62. Weber R, Ruppik M, Rickenbach M, Spoerri A, Furrer H, Battegay M, et al. Decreasing mortality and
changing patterns of causes of death in the Swiss HIV Cohort Study. HIV medicine. 2013, 14: 195–
207. https://doi.org/10.1111/j.1468-1293.2012.01051.x PMID: 22998068
63. Mothobi NZ, Brew BJ. Neurocognitive dysfunction in the highly active antiretroviral therapy era. Current
opinion in infectious diseases. 2012; 25: 4–9. https://doi.org/10.1097/QCO.0b013e32834ef586 PMID:
22156897
64. Grinsztejn B, Luz PM, Pacheco AG, Santos DV, Velasque L, Moreira RI, et al. Changing mortality profile
among HIV-infected patients in Rio de Janeiro, Brazil: shifting from AIDS to non-AIDS related conditions
in the HAART era. PloS One. 2013; 8: e59768. https://doi.org/10.1371/journal.pone.0059768 PMID:
23577074
65. Young F, Critchley JA, Johnstone LK, Unwin NC. A review of co-morbidity between infectious and
chronic disease in Sub Saharan Africa: TB and diabetes mellitus, HIV and metabolic syndrome, and the
impact of globalization. Global Health. 2009; 5: 9. https://doi.org/10.1186/1744-8603-5-9 PMID:
19751503
66. Sagwa EL, Nunurai RN, Mavhunga F, Rennie T, Leufkens HGM, Teeuwisse AKM. Comparing amikacin
and kanamycininduced hearing loss in multidrug-resistant tuberculosis treatment under programmatic
conditions in a Namibian retrospective cohort. BMC Pharmacology and Toxicology (2015) 16:36
https://doi.org/10.1186/s40360-015-0036-7 PMID: 26654443
67. Obasikene G, Adobamen P, Okundia P, Ogusi FO. Prevalence of ototoxicity in University of Benin
Teaching Hospital, Benin city: a 5-year review. Niger J Clin Pract. 2012 Oct-Dec; 15(4):453–7. https://
doi.org/10.4103/1119-3077.104527 PMID: 23238197
68. Coombes Rebecca. Developed world is robbing African countries of health staff. Br Med J. 2005; 330
(7497): 927
69. World Health Organization. Research for universal health coverage: World Health Organization report
2013. http://www.who.int/whr/2013/report/en/. Accessed on 1st/07/2017.
Addressing the under-reporting of adverse drug reactions in public health programs
PLOS ONE | https://doi.org/10.1371/journal.pone.0200810 August 22, 2018 14 / 14